Pharmacology (from a Greek
word “φάρμακον”, Pharmakon, means drug and “-λογία”,-logia)
is the science which deals with the study of drugs actions. It can be
subdivided into Pharmacokinetics (PK) and Pharmacodynamics (PD).
Firstly, Pharmacokinetics
(“-Kinetikos” meaning putting in motion and the study of time dependency) is a
branch of pharmacology and dedicated to the determination of the fate of
substances which are administered. It can be divided into several branches including
the extent and the rate of absorption, distribution,
metabolism and elimination [ADME]. Also, liberation, drug release of the dosage form, can be
added to them according to the recent studies, to make PK can be better
described as [LAMDE].
Secondly, Pharmacodynamics is the study of the
biochemical and the physiological effects of drugs, mechanisms of drugs actions
and the relationship between drug concentration and its effect.
PK: what the body does to a drug
PD: what a drug does to the body
All drugs must bind to receptors to bring about an effect.
However, at the molecular level, drug binding to a receptor is only the first step in what is
often a complex sequence of steps.
A receptor is a protein molecule, embedded in either (A)the plasma
membrane [transmembrane] or (B)cytoplasm of the cell, to which a mobile signalling molecule
(Ligand) may attach.
There are many types of receptors and the main receptor families are:
1-Ion channels [IC]: (Also
referred to ionotropic receptors or channel-linked receptors)
a. Ligand gated IC b. Voltage gated IC c. Second messenger regulated IC.
They are a group of transmembrane
ion channels that are opened and closed in response to the binding of
messenger.
ex: Cholinergic nicotinic
receptors
2- G-protein- coupled receptors
[GPCR]: (Also referred to seven-transmembrane domain receptors, 7TM, or
heptahelical receptors and Serpentine [snaky movement around the membrane]
receptors)
They are a large protein family of transmembrane receptor that sense
molecules outside the cell and activate inside signal transduction pathways
and, ultimately, cellular responses. G protein-coupled receptors are found only
in eukaryotes, including yeast, plants, and animals. The ligands hat bind and
activate these receptors include light-sensitive compounds, odours,
pheromones, hormones, and neurotransmitters, and vary in size from small molecules to
peptides to large proteins. G protein-coupled receptors are involved in many
diseases, and are also the target of around half of all modern medicinal drugs.
ex: α and β-adrenoreceptors
3- Enzyme-linked receptors:
They are transmembrane
receptors, where the binding site of an extracellular ligand causes enzymatic
activity on the intracellular side. They have two important domains, an
extra-cellular ligand binding domain and an intracellular domain, which has a
Catalytic function.
ex: Insulin receptors
4- Intracellular receptors:
They are receptors located inside the cell rather than on its cell membrane. Examples are the class of nuclear receptors located in the cell nucleus and the IP3 receptor located on the endoplasmic reticulum. The ligands that bind to them are usually intracellular second messengers like inositol trisphosphate (IP3) and extracellular lipophilic hormones like steroid hormones. Some intracrine peptide hormones also have intracellular receptors.
ex: Steroid receptors
They are receptors located inside the cell rather than on its cell membrane. Examples are the class of nuclear receptors located in the cell nucleus and the IP3 receptor located on the endoplasmic reticulum. The ligands that bind to them are usually intracellular second messengers like inositol trisphosphate (IP3) and extracellular lipophilic hormones like steroid hormones. Some intracrine peptide hormones also have intracellular receptors.
ex: Steroid receptors
- All the previous receptor types can be presented in the following diagram:
Spare receptors
When a drug binds to its specific
receptor, there will be a conformational change in that receptor's shape. That
change is one of many steps [transduction process] before any cellular response
occur due to that drug. The term of
transduction process which links between drug occupancy of receptors and its
pharmacological response is called coupling. The relative efficiency of
occupancy-response is partially determined by the initial conformation change.
By this way full agonist are more efficiently coupled than partial agonist. On
the regular basis, the biological response of the drug is based on the number the
receptors which bound to that drug. Although that, sometimes the biological
response is more complex to depend on the number of receptors only. That can be
cleared by talking about receptor linked to enzymatic transduction cascades.
At which the biological response increases with no any relation with the number
of the receptors. As a result of that
there will be a non-linear relation between occupancy-response. Many
factors may contribute to that and they are partially understood. But the term
“spare receptors” may give the basic picture about that phenomenon.
Spare receptor can elicit the maximal response of the agonist without occupy
all available complement receptors.
>>The existence of a spare receptor
may belong to 1 of the 2 following mechanisms:
1- The duration of activation of
the effector is much greater than the duration of drug-receptor activation.
2- The actual number of excising receptors may exceed the
number of effector [spare in number]
- There are three aspects of drug-receptor function:
A. Receptors largely determine the
quantitative relations between dose or conc. of a drug and its pharmacological response. This is based on the receptor’s affinity to bind and it’s
abundance in target cells and tissues.
Drug response based on:
-Affinity of the drug
to the receptor
- Drug efficacy
B. Receptors mediate the actions of drug to be either agonist and antagonist.
C. Receptors are responsible for selectivity of the drug
action.
- Types of Drug-Receptor interactions:
Different resultant
pharmacological responses are due to different drug molecules. Whereas difference
in drug’s structure results in alteration of the main effect.
*Agonist drugs: [Full agonist]
They bind to and activate the receptor either directly or
indirectly.
Directly: by a direct binding to the receptor.
Indirectly: by inhibiting the molecules responsible
for terminating the action of an endogenous agonist. For instance, acetylcholinesterase inhibitors
[such as insecticides].
*Antagonist
drugs:
They bind to the receptor BUT they do not activate it. For
example, acetylcholine receptor blockers [such as Atropine].
*Partial
agonist drugs:
They bind to the receptor and activate it BUT they do
not evoke as great a response as
so-called full agonists. Such as, some of β-blockers [such as Pindolol].
Drug action related definitions
There are two factors
which control drug action:
- Drug’s affinity.
- Drug’s intrinsic activity (efficacy)
Drug's affinity:
Affinity is a measure
of tendency of the drug to bind to its receptor. For instance, in case
of Kd when it is low, that means that drug has high affinity to that
receptor.
Drug’s intrinsic activity:
It is a measure of
the ability of a drug once bound to the receptor to generate an effect of the
activating stimulus and producing a change in cellular activity. It is
different whereas a drugs is agonist, antagonist,or partial agonist.
Drug’s affinity and intrinsic activity are independent properties. Agonists have both but antagonists have only affinity.
Drug’s affinity and intrinsic activity are independent properties. Agonists have both but antagonists have only affinity.
Potency of a drug:
Potency is the dose (amount) of the drug in relation to its
effect. It is determined mainly by the affinity of the drug to its receptor
and the number of available receptors. It is seldom an important clinical considerations.
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